Impact of encorafenib on survival of patients with BRAF^V600E-mutant metastatic colorectal cancer in a real-world setting

Colorectal cancer (CRC) is the third most prevalent cancer and the second leading cause of cancer related death in western countries (Bray et al. 2018). Resection of the primary tumour with or without systemic adjuvant chemotherapy is a curative option in patients with local or locally advanced disease. However, up to 50% of patients initially present with distant metastases or develop distant relapse. Systemic chemotherapy is the primary choice of treatment for patients not amenable to curative surgery or metastasectomy. A comprehensive molecular profiling including mutational analysis of KRAS (Kirsten rat sarcoma virus), NRAS (neuroblastoma RAS viral oncogene homolog), BRAF (RAS-associated factor B) and dMMR/MSI (deficient mismatch repair/microsatellite instability) is recommended before initiation of systemic palliative treatment (Benson et al. 2021). In addition, primary tumour localization (right sided vs left sided) has an impact on prognosis and efficacy of several drugs and should be considered before the initiation of first-line systemic treatment (Arnold et al. 2017). Mutations of the KRAS or NRAS oncogene are detected in up to 55% of all mCRCs and are strong negative predictors for the efficacy of monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) (Stintzing et al. 2017; Venook et al. 2017). Thus, patients with KRAS- or NRAS-mutant tumours should be treated with a chemotherapy doublet (FOLFOX or FOLFIRI) or triplet (FOLFOXIRI) in combination with the anti-angiogenic antibody bevacizumab targeting the vascular endothelial growth factor A (VEGFA) in first line. Patients with mCRC without KRAS or NRAS mutations (all RAS wildtype) should be treated with a chemotherapy doublet in combination with an EGFR antibody (cetuximab or panitumumab) rather than with bevacizumab in first line. However, efficacy of EGFR antibodies seems to be restricted to patients whose primary tumour is located on the left site of the colon, whilst patients harbouring a tumour situated proximal from the left splenic flexure should rather receive bevacizumab in first line (Arnold et al. 2017).

Mutations of the BRAF oncogene, primarily BRAF^V600E, are detected in up to 10% of patients with colorectal cancer (Fransen et al. 2004; Souglakos et al. 2009; Roth et al. 2010; Yokota et al. 2011; Clancy et al. 2013; Sinicrope et al. 2015). Colorectal cancers with BRAF^V600E mutations are clinically different from tumours without BRAF mutations and also from tumours harbouring non-V600 mutations (Jones et al. 2017). BRAF^V600E-mutant tumours are more frequently observed in female patients and situated right-sided (Loupakis et al. 2016). Additionally, these tumours are associated with a poor histopathological grading, MSI^high/dMMR status, larger primary tumour size, higher rate of nodal metastases and peritoneal carcinomatosis. Patients with BRAF^V600E-mutant metastatic CRC have a dismal prognosis with a reduced response to chemotherapy and dramatically reduced overall survival time of only 1 year in clinical trials (Cremolini et al. 2015; Modest et al. 2016; Stintzing et al. 2017).

The best treatment strategy in this poor prognostic subgroup of patients with BRAF^V600E-mutant mCRC remains elusive. Current clinical guidelines recommend a triplet chemotherapy with FOLFOXIRI in combination with bevacizumab as preferred first-line chemotherapy in fit patients (Van Cutsem et al. 2016). However, these recommendations were based on a small retrospective subgroup analysis of 28 patients treated within the TRIBE study (Cremolini et al. 2015). In this study, the triplet chemotherapy with FOLFOXIRI plus bevacizumab was superior to the doublet with FOLFIRI plus bevacizumab. Recently, pooled analyses of 5 clinical trials which tested the triplet FOLFOXIRI plus bevacizumab versus a doublet chemotherapy with FOLFOX or FOLFIRI plus bevacizumab showed comparable median overall survival with the triplet (13.6 months) or the doublet chemotherapy (14.5 months) in at least 115 patients with BRAF^V600E-mutated metastatic CRC (Cremolini et al. 2020). In a real-world setting, a substantial number of patients do not qualify for the triplet chemotherapy with FOLFOXIRI due to age, reduced performance status or comorbidities. The efficacy of EGFR directed antibodies (cetuximab, panitumumab) in BRAF^V600E-mutated mCRC has been discussed controversially (Pietrantonio et al. 2015; Rowland et al. 2015). Retrospective post-hoc meta-analyses of large clinical trials did not show conclusive results. However, the recently published FIRE4.5 study demonstrated that the triplet chemotherapy with a modified FOLFOXIRI plus the EGFR antibody cetuximab was inferior to FOLFOXIRI plus bevacizumab in first-line setting (Stintzing et al. 2021). Interestingly, after failure of cytotoxic chemotherapy, the combination of the BRAF inhibitor encorafenib and the monoclonal EGFR antibody cetuximab is effective in patients with BRAF^V600E-mutant mCRC. In the randomized phase III BEACON trial, this combination was superior to a standard systemic chemotherapy and became the new standard for previously treated patients (Kopetz et al. 2019).

In the above-reported prospective clinical trials, only patients in good performance status without significant comorbidities were enrolled. The results of these trials are thus not fully applicable to patients treated in a real-world setting. Treatment strategies in patients not fulfilling generic study inclusion criteria have to be defined. Against this background, we report the clinical course of a cohort of 51 patients with BRAF^V600E-mutant mCRC who consulted our centre and received palliative treatment irrespective of predefined capability criteria such as performance status, age, comorbidities or laboratory values as required for clinical trial inclusion. The aim of this retrospective study is to define the best treatment strategy in this poor prognostic patient population. Further, we wanted to evaluate the impact of the introduction of BRAF inhibitor treatment in a real-world setting.

Here, we report the clinical outcome of unselected patients with BRAF^V600E-mutant mCRC, treated with palliative systemic therapy at a large comprehensive cancer centre. In contrast to prospective clinical trials in mCRC, we included patients irrespective of age, EOCG performance status, laboratory abnormalities or comorbidities in this retrospective analysis. The aim of this study was to identify the best treatment strategies for this poor prognostic patient population. As previously reported, patient characteristics were enriched with female sex, right-sided primary tumour, higher TNM stage at diagnosis and poor grading (G3) (Roth et al. 2010; Yamauchi et al. 2012; Clancy et al. 2013; Sinicrope et al. 2015; Wang et al. 2019). Most patients received a palliative doublet chemotherapy with FOLFOX or FOLFIRI in combination with bevacizumab as first line. Only a quarter (23.5%) of our real-world patients qualified for the intensive triplet FOLFOXIRI chemotherapy plus bevacizumab and were treated according to the current guidelines. These findings underline the challenges posed by the actual guidelines in a real-world patient population. However, those patients who received FOLFOXIRI had a median PFS of 13.0 months, which was comparable to the median PFS reported in the pivotal TRIBE study and significantly higher than in those patients who received a different first-line therapy (Cremolini et al. 2015). Furthermore, the ORR of 72.7% achieved with FOLFOXIRI was comparable to the control arm with FOLFOXIRI plus bevacizumab in the recently presented FIRE4.5 study (Stintzing et al. 2021). The median OS of 22.1 months in those FOLFOXIRI-treated patients was encouraging but it was not significantly higher compared to patients, receiving a different first-line therapy. This is in line with the recently published meta-analyses of 5 prospective randomized clinical trials in patients with mCRC, which investigated the additional benefit of the triplet chemotherapy with FOLFOXIRI plus bevacizumab versus a doublet with FOLFOX or FOLFIRI plus bevacizumab (Cremolini et al. 2020). In the subgroup of patients with BRAF^V600E−mutant mCRC, the median OS was identical in patients who received a triplet or doublet first-line chemotherapy (13.6 vs. 14.5 months). Thus, the optimal first-line therapy in this poor prognostic patient population remains elusive. A doublet chemotherapy seems to be an appropriate alternative to FOLFOXIRI, in particular since the majority of patients in a real-world setting do not qualify for an intensive triplet chemotherapy. However, we recommend the addition of bevacizumab to the first-line chemotherapy backbone based on the results we observed in our patient population. Patients who received a monoclonal antibody had a higher ORR, median PFS and median OS compared to patients treated with chemotherapy only.

Interestingly, the median OS of 17.6 months in our unselected patient population was markedly higher than in the reported pooled analysis of Cremolini et al. and comparable to the recently reported data from the control arm with FOLFOXIRI plus bevacizumab of the FIRE4.5 trial (17.1 months) (Cremolini et al. 2020; Stintzing et al. 2021). This unexpectedly high median OS could be explained by the high number of patients, who had access to targeted therapies after progression following first-line therapy at our centre within clinical trials, as off-label use or later after the approval of encorafenib and cetuximab. In total, one third of our patients (18 out of 51) received a BRAF inhibitor in combination with an EGFR antibody or a different second targeted agent during the course of therapy. The median PFS in patients who received a BRAF inhibitor was 4.1 months and thus comparable to the median PFS observed in the pivotal BEACON trial with encorafenib and cetuximab (4.3 months) (Kopetz et al. 2019). Interestingly, the median PFS of 4.0 months in those patients receiving a standard chemotherapy in second-line in our cohort was comparable to the median PFS with encorafenib and cetuximab and markedly higher than the reported PFS of the control arm with cetuximab and irinotecan or FOLFIRI in the BEACON trial. This could be explained by the fact that only 3 patients in our cohort received an EGFR antibody in combination with cytotoxic chemotherapy and most patients were rather treated with a chemotherapy doublet in combination with an anti-angiogenic agent (bevacizumab or aflibercept) in second-line. A retrospective post-hoc molecular subgroup analyses of patients with BRAF^V600E-mutated mCRC treated in the RAISE study, which evaluated the addition of the anti-angiogenic antibody ramucirumab to FOLFIRI in second line, also showed a median PFS of 5.7 months with a median OS of 9.0 months (Yoshino et al. 2019). Thus, cytotoxic chemotherapy should be rather combined with an anti-angiogenic agent rather than with an EGFR antibody in BRAF^V600E-mutant mCRC patients. This was recently confirmed by the FIRE4.5 study which showed a superiority of bevacizumab versus cetuximab in first-line therapy with FOLFOXIRI.

Notably, in our cohort patients who received a BRAF inhibitor in combination with an EGFR antibody or a different targeted second agent had an extraordinarily high median OS of 25.1 months from start of their palliative treatment compared to only 13.1 months in those patients who received cytotoxic chemotherapy only. Thus, this treatment strategy should implicitly be integrated in the treatment algorithm of patients with BRAF^V600E-mutant mCRC.

In conclusion, only a small number of patients with BRAF^V600E-mutant mCRC in a real-world setting qualify for the guideline recommended intensive first-line chemotherapy with FOLFOXIRI and are rather treated with a doublet chemotherapy in combination with bevacizumab. Even though the PFS in first line is prolonged with the triplet chemotherapy compared to other less intensive protocols, it has no significant impact on OS and a doublet chemotherapy with FOLFOX or FOLFIRI in combination with bevacizumab is an appropriate alternative. After progress to cytotoxic chemotherapy, the integration of a BRAF inhibitor in combination with an EGFR antibody into the treatment strategy in a real-world setting is feasible and highly recommended. Encouraging median OS times could be achieved in a real-world setting if patients have early access to these molecular targeted therapies.